Hepatocellular cancer (HCC) is common in liver transplant recipients. Can the liver cancer be resected while waiting for a liver transplant?

1. --Harshal Rajekar

2. ….Why?
We do see many a patient with recurrent hepato-cellular
cancer after liver resection.
Especially in the setting of a chronic Liver disease….
Hep B, Hep C, ETOH liver disease……etc.
Quite a few patients are unable to undergo L Tx due to
extensive disease, and probably the chances of recurrence
after LTx would be increased in the event of aggressive
HCC.
Often the extent of liver cirrhosis is not apparent on
clinical grounds alone. Having had a look at the liver at
surgery, and of course, the microscopic assessment of the
activity of the liver disease, affords a better judgement.

3. ……Liver Transplant for HCC?
Liver transplantation is accepted as the treatment of
choice for HCC in cirrhotics.
Defined criteria for transplantation in HCC,
- Milan criteria.
- UCSF criteria.
Attempt to extend criteria beyond the existing ones
has met with reasonable success.
Provides the best chance of long term cure, with
treatment of the primary liver problem.

4. What is the optimal treatment for Hepatocellular Cancer
in patients with Liver disease?
Evidence in literature that Liver transplantation
resection have similar 5-year survival after treatment
for HCC. (in Child’s A patients)
However, 5-yr recurrence free survival is dismal after
resection, as compared to liver transplantation.
But patients assigned to the waiting list for
transplantation for HCC stand the risk of drop-out or
disease progression while waiting.

5. Poon RT, Fan ST, Lo CM, Liu CL, Wong J.
Difference in tumor invasiveness in cirrhotic patients with hepatocellular
carcinoma fulfilling the Milan criteria treated by resection and
transplantation: impact on long-term survival.
Ann Surg. 2007 Jan;245(1):51-8.
Multivariate analysis showed that hepatitis C virus serology,
tumor size, tumor number, and microscopic venous invasion,
but not resection or transplantation, were of prognostic
significance.
There were significant differences in tumor invasiveness in HCC
treated by transplantation and resection as a result of selection
bias, even in patients with the tumors fulfilling the Milan
criteria.
When the different tumor invasiveness was taken into account,
there was no significant difference in the long-term survival
after resection or transplantation.

6. Resection v/s primary liver transplantation…..
RESECTION OF HCC:
Patients assignedto liver transplant waiting lists run the
risk of not receiving a donorliver, in which case their
survival is predicted to be poor.
Survival after resection in a group of patients with
advancedtumors is worse than that after transplantation.
Recurrent HCC occurs in 50% to 80% of patients at 5 years
after resection, with the majority occurring within 2 years.
LIVER TRANSPLANT:
Transplantation seems to be superior because it treats
the underlying liver disease and the HCC.

7. Drawbacks of Liver transplantation for
HCC……
?progression of disease/ drop-out while on waiting list.
Shortage of donor organs.
Risk to living donor in case of LDLT.
Cost of transplant surgery.
Long term immuno-suppression.
And, the same factors responsible for high recurrence rates afterAnd, the same factors responsible for high recurrence rates after
surgical resection of hepato-cellular- cancer; are implicatedsurgical resection of hepato-cellular- cancer; are implicated
for high recurrence rates after liver transplant. ….. Viz,for high recurrence rates after liver transplant. ….. Viz,
vascular invasion, large tumour size, poorly differentiatedvascular invasion, large tumour size, poorly differentiated
tumors and serosal involvement at the time of surgery.tumors and serosal involvement at the time of surgery.

8. Possible predictors of recurrence of HCC after
resection on the background of pre-existing Liver
disease…..
Various indices have been described to predict the risk of
recurrence/ prognosis of HCC after resection……
1. CLIP (Cancer of the Liver Italian Program).
2. BCLC (Barcelona Clinic Liver Cancer) staging.
3. Okuda classification.
4. TNM , the AJCC staging system.
5. CUPI (Chinese Univ. Prognostic Index).
6.JIS (Japanese Integrated Score) system.
7. S Li De score (stage, liver damage and des-gamma-
prothrombin level).
8. ?MELD score.

9. TW Chen, et al (Taiwan)
European Journal of Surgical Oncology ;
Volume 33, Issue 4, May 2007, Pages 480-487.
In our patient cohort, the CLIP and JIS systems gave better results
than did the other staging systems. The discriminatory ability of
the CLIP and JIS staging for death, evaluated by ROC curve
areas, was also better. In the subgroups of major hepatectomy
patients with a non-cirrhotic liver or minor hepatectomy
patients with a cirrhotic liver, the CLIP and JIS systems showed
similar better performances in these three tests. The
discriminatory ability of the CLIP system was the best in major
hepatectomy patients with a non-cirrhotic liver while JIS score
discriminated best in minor hepatectomy patients with a
cirrhotic liver.
Thus, scoring systems which consider tumour factors, inThus, scoring systems which consider tumour factors, in
addition to severity of the background liver disease areaddition to severity of the background liver disease are
better able to predict the prognosis after resectionbetter able to predict the prognosis after resection..

10. Shirabe K, and others; (Japan)
Clinicopathological risk factors linked to recurrence pattern after curative hepatic
resection for hepatocellular carcinoma--results of 152 resected cases.
Hepatogastroenterology 2007 Oct-Nov; 54(79):2084-7.
The risk factors for patients with >4nodules were high levels of ALT,
low Albumin, high values in the ICG retention test at fifteen minutes,
hepatitis C antibody positivity. low platelet counts, and high
histological hepatitis activity. The risk factors for patients with <4
nodules were large tumor size, histological presence of vascular
invasion by cancer cells, intrahepatic metastasis, and poor
differentiation.
CONCLUSIONS: The risk factors linked to recurrence with no more
than three HCC nodules recurrence were related to host-related
factors such as hepatic function, and hepatitis activity, but not tumor
related. The risk factors linked to multiple recurrence were tumor
related. The analysis of recurrence patterns revealed that completely
different mechanisms exist in the patients with recurrence involving
no more than four nodules, which may be related to multicentric
occurrence, and patients with multiple recurrence, which may be
related to the metastasis of cancer cells.

11. Risk Factors for Different Patterns of RecurrenceRisk Factors for Different Patterns of Recurrence
after Resection of Hepatocellular Carcinoma:after Resection of Hepatocellular Carcinoma:
Kaibori, et al; Kansai Med Univ.; Japan described in Anticancer
Res. 2007 Jul-Aug;27(4C):2809-16.
higher levels of protein induced by absence/antagonism of
vitamin K-II,
larger tumors,
more poorly differentiated tumors,
intravascular invasion,
Younger patients,
Activity of liver disease ……..
All these co-related with prognosis, and recurrence withAll these co-related with prognosis, and recurrence with
aggressive disease.aggressive disease.

12. Salvage transplantation
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
Secondary transplantation.


Both terms have been used interchangeably causing some
confusion in drawing up conclusions………

13. Sala M, Fuster J, et al; Barcelona Clinic Liver Cancer (BCLC) Group.
High pathological risk of recurrence after surgical resection for hepatocellular
carcinoma: an indication for salvage liver transplantation.
Liver Transpl. 2004 Oct;10(10):1294-300.
1. 2 major pathways leading to recurrence: tumor dissemination prior
to operation and de novo tumor development in an oncogenic
cirrhotic liver.
2. With recurrence, less than 20% of the patients are candidates for
salvage L Tx.
3. The risk of recurrence can be accurately predicted by pathologic
examination of the resected tissue. Micro-vascular invasion and
presence of satellite nodules are thought to be related to
unrecognized tumor spread prior to resection, and interestingly,
those transplanted patients in whom pathology examination depicts
these pathologic high risk parameters do not present a prohibitive
rate of disease recurrence during follow-up.

14. …the findings…..:-
During the period of the investigation, we operated on 77 patients and
17 of them qualified as candidates both for resection and LT.
According to our treatment strategy, they were offered resection as
primary treatment, and based on the pathologic findings, 8 patients
were classified at high risk and 9 at low risk. All but 1 of those at high
risk showed recurrence either prior to LT (n = 2) or in the explanted
liver in the absence of disease on imaging techniques (n = 3). 2
patients did not accept to be enlisted who developed multi-focal
recurrence.
In addition, we have also evidenced that this policy offers an adequate
long-term outcome. Only 1 patient developed massive or extensive
tumor dissemination after LT and died 4 months after the operation.
The other 4 patients have been followed for a median of 45 months
and show no tumor recurrence, there being only 1 death at 84 mths
due to recurrent HCV cirrhosis.
On the other hand, the outcome of patients classified as low risk has
also been encouraging. Only 2 out of the 9 patients in this group have
recurrence.

15. Probable advantages of this approach……:-
1. Could serve as a bridge to liver transplant for those candidates
who are deemed suitable.
2. The initial resection of the tumour gives an accurate histo-
pathological analysis of the tumour, and the underlying
cirrhosis… i.e. grade of tumour, differentiation, micro- and
macro-vascular invasion, lymphatic invasion, mitotic activity,
satellite nodules, margins of resection and also the activity of
background liver disease (inflammation/ viral hepatitis).
3. Most patients with chronic viral hepatitis in Childs A status,
the severity of the background liver disease is not clinically
apparent.
4. Patients are divided into low-risk and high risk for recurrence
groups. Those in the low risk (not offered L Tx) can be offered
a transplant if and when recurrent disease is found.

16. Disadvantages of transplantation after
resection of HCC….:-
Surgery technically more difficult.
Increased peri-operative blood transfusion
requirement.
Increased operative time, and cost.
Increased time needed in ICU.
Increased peri-operative morbidity and mortality .
Recurrence rates are probably higher once
natural selection bias has been ruled out…. And
depend on tumour charachteristics.